Currently, cephalosporin/semi-synthetic penicillins, fluoroquinolones and macrolides are the three first-line drugs in global anti-infective market, accounting for 80% of the anti-infective market shares. Among them, the international market share of macrolide antibiotics, led by the third generation of erythromycin, such as azithromycin, clarithromycin and roxithromycin, has increased steadily in recent years. Currently, China is the biggest manufacturer of macrolide antibiotic raw materials in the world, and the total macrolide antibiotic raw material production reaches more than 10,000 tons, which accounts for ⅔ of world total production.
Erythromycin thiocyanate, mainly used for treating infection against G+ bacterial, mycoplasma and chlamydia etc., is the raw material for preparing erythromycin derivative products, such as azithromycin, clarithromycin and roxithromycin in China. Erythromycin thiocyanate becomes the third leading product in the world antibiotic market due to a large number of clinical applications of erythromycin, erythromycin derivatives and downstream products thereof. Therefore, the corresponding raw materials have a broad market space. The quality and content of erythromycin thiocyanate are measured by detecting the content of main component erythromycin A. The detection method is included in Chinese Pharmacopoeia 2005 edition. As the skilled person in this art known, although there are many manufacturers providing the raw materials, the quality of which is uneven. Chen Yue detected the content of the main component erythromycin of two samples from two different companies, and the contents were found to be 68.2%˜71.8% and 73.8%˜76.0% (Determination of Erythromycin Thiocyanate and Its Related Substances by Reverse Phase-High Performance Liquid Chromatography, Chinese Pharmaceutical Journal, 2007, 42 (23)). Wei Qi et al. reported the content of erythromycin A, the main component of erythromycin thiocyanate, was found to be 68.7%˜70.5% (Determination of Erythromycin Thiocyanate Component by Reverse Phase-High Performance Liquid Chromatography, Public Medical Forum Magazine, 2009, 13). The skilled person in the art knows that the product with poor quality refers to the product with the content of the main component erythromycin A to be less than 72%. Erythromycin A can only be used as a veterinary drug. Even with the use of raw materials with better quality in producing the derivatives, the quality of derivatives is also uneven because of their different qualities of the raw materials. Only those products that have low cost and high quality can take up favorable competitive advantage in the market.
Erythromycin thiocyanate comprises erythromycin thiocyanate A as shown in formula I, erythromycin thiocyanate B, erythromycin thiocyanate C and other related impurities. Erythromycin thiocyanate A is the desired product and other components are all impurities. These impurities can be co-crystallized during the crystallization of erythromycin thiocyanate A or absorbed on crystal itself resulting in product with high impurity content. The level of the impurity content is not only closely related to the condition of crystallizing process, but also the kinds of solvents.

Erythromycin thiocyanate A and the impurities like erythromycin thiocyanate B, C, D and E have different groups in molecular structure resulting in different polarities among them. Therefore, they have different solubilities in different solvents with different polarities. In order to improve the product purity, a suitable solvent system with high solubility of impurities should be selected in which the impurities would not co-crystallize with erythromycin thiocyanate A or would only precipitate a very small amount. Moreover, the kind of solvent also has an influence on the appearance of crystals. Good crystal properties favor filtration, separation, washing and drying.
In prior art, generally, solvent extraction or fixed bed adsorption was used to obtain a solution of erythromycin with butyl acetate, octanol or some mixed water-insoluble solvents. After the solution was separated, washed and filtrated, thiocyanate aqueous solution was added, stirred and mixed. Then acetic acid was added slowly to obtain the crystal slurry of erythromycin thiocyanate. The crystal slurry was centrifuged and washed to obtain wet erythromycin thiocyanate. The wet erythromycin thiocyanate was then crushed and dried to obtain erythromycin thiocyanate product. Chinese patent CN 200810179653.5 also disclosed the use of butyl acetate as a solvent.
The methods in prior art have disadvantages. The amount of erythromycin thiocyanate A in the product prepared according to the methods in prior art was less than 78%. Because of its low purity with large amount of impurities, the product cannot be used as the starting material which meets the EU and US standard for synthesizing the derivatives like azithromycin and clarithromycin.